NADPH Oxidase NOX4 Is a Critical Mediator of BRAF ^V600E -Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas

Abstract

Here, using two human BRAF^V600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAF^V600E in a conditional manner, we show that NOX4 upregulation is controlled at the transcriptional level by the oncogene via the TGF-β/Smad3 signaling pathway. Importantly, treatment of cells with NOX4-targeted siRNA downregulates BRAF^V600E-induced NIS repression. Innovation and Conclusion: Our results establish a link between BRAF^V600E and NOX4, which is confirmed by a comparative analysis of NOX4 expression in human (TCGA) and mouse thyroid cancers. Remarkably, analysis of human and murine BRAF^V600E-mutated thyroid tumors highlights that the level of NOX4 expression is inversely correlated to thyroid differentiation suggesting that other genes involved in thyroid differentiation in addition to NIS might be silenced by a mechanism controlled by NOX4-derived ROS. This study opens a new opportunity to optimize thyroid cancer therapy. Antioxid. Redox Signal. 26, 864-877.